Latent profiles of substance use, early life stress, and attention/externalizing problems and their association with neural correlates of reinforcement learning in adolescents.

BACKGROUND: Adolescent substance use, externalizing and attention problems, and early life stress (ELS) commonly co-occur. These psychopathologies show overlapping neural dysfunction in the form of reduced recruitment of reward processing neuro-circuitries. However, it is unclear to what extent these psychopathologies show common v. different neural dysfunctions as a function of symptom profiles, as no studies have directly compared neural dysfunctions associated with each of these psychopathologies to each other. METHODS: In study 1, a latent profile analysis (LPA) was conducted in a sample of 266 adolescents (aged 13-18, 41.7% female, 58.3% male) from a residential youth care facility and the surrounding community to investigate substance use, externalizing and attention problems, and ELS psychopathologies and their co-presentation. In study 2, we examined a subsample of 174 participants who completed the Passive Avoidance learning task during functional magnetic resonance imaging to examine differential and/or common reward processing neuro-circuitry dysfunctions associated with symptom profiles based on these co-presentations. RESULTS: In study 1, LPA identified profiles of substance use plus rule-breaking behaviors, attention-deficit hyperactivity disorder, and ELS. In study 2, the substance use/rule-breaking profile was associated with reduced recruitment of reward processing and attentional neuro-circuitries during the Passive Avoidance task (p < 0.05, corrected for multiple comparisons). CONCLUSIONS: Findings indicate that there is reduced responsivity of striato-cortical regions when receiving outcomes on an instrumental learning task within a profile of adolescents with substance use and rule-breaking behaviors. Mitigating reward processing dysfunction specifically may represent a potential intervention target for substance-use psychopathologies accompanied by rule-breaking behaviors.

Use of Marijuana: Effect on Brain Health: A Scientific Statement From the American Heart Association.

Marijuana is perceived as a harmless drug, and its recreational use has gained popularity among young individuals. The concentration of active ingredients in recreational formulations has gradually increased over time, and high-potency illicit cannabinomimetics have become available. Thus, the consumption of cannabis in the general population is rising. Data from preclinical models demonstrate that cannabinoid receptors are expressed in high density in areas involved in cognition and behavior, particularly during periods of active neurodevelopment and maturation. In addition, growing evidence highlights the role of endogenous cannabinoid pathways in the regulation of neurotransmitter release, synaptic plasticity, and neurodevelopment. In animal models, exogenous cannabinoids disrupt these important processes and lead to cognitive and behavioral abnormalities. These data correlate with the higher risk of cognitive impairment reported in some observational studies done in humans. It is unclear whether the effect of cannabis on cognition reverts after abstinence. However, this evidence, along with the increased risk of stroke reported in marijuana users, raises concerns about its potential long-term effects on cognitive function. This scientific statement reviews the safety of cannabis use from the perspective of brain health, describes mechanistically how cannabis may cause cognitive dysfunction, and advocates for a more informed health care worker and consumer about the potential for cannabis to adversely affect the brain.

Residual Effects of Cannabis Use on Effort-Based Decision-Making.

OBJECTIVE: Acute Δ9-tetrahydrocannabinol (THC) administration in humans (Lawn etal., 2016) and rats (Silveira, Adams, Morena, Hill, & Winstanley, 2016) has been associated with decreased effort allocation that may explain amotivation during acute cannabis intoxication. To date, however, whether residual effects of cannabis use on effort-based decision-making are present and observable in humans have not yet been determined. The goal of this study was to test whether prolonged cannabis use has residual effects on effort-based decision-making in 24-hr abstinent cannabis using adults. METHOD: We evaluated performance on the Effort Expenditure for Reward Task (EEfRT) in 41 adult cannabis users (mean age = 24.63 years, 21 males) and 45 nonusers (mean age = 23.90 years, 19 males). A mixed 2x3x3 ANOVA with age as a covariate was performed to examine the effect of group, probability of winning, and reward amount on EEfRT performance. EEfRT performance was operationalized as % of trials for which the hard (vs. easy) condition was chosen. Pearson's correlations were conducted to test the relationship between EEfRT performance and measures of cannabis use, anhedonia and motivation. RESULTS: We found that cannabis users selected hard trials significantly more than nonusers regardless of win probability or reward level. Frequency of cannabis use was positively correlated with amount of % hard trials chosen. There were no significant correlations between % hard trials chosen, self-reported anhedonia, or motivation. CONCLUSIONS: These results suggest that unlike acute effects, residual effects of cannabis following 24 hrs of abstinence are associated with greater effort allocation during effort-based decision-making.

Alcohol use disorder and cannabis use disorder symptomatology in adolescents is associated with dysfunction in neural processing of future events.

Two of the most commonly used substances by adolescents in the United States are cannabis and alcohol. Cannabis use disorder (CUD) and alcohol use disorder (AUD) are associated with impairments in decision-making processes. One mechanism for impaired decision-making in these individuals is thought to be an inability to adequately represent future events during decision-making. In the current study involving 112 adolescents, we used a comparative optimism task to examine the relationship between relative severity of CUD/AUD (as indexed by the CUD/AUD Identification Tests [CUDIT/AUDIT]) and atypical function within neural systems underlying affect-based neural represenation future events. Greater CUDIT scores were negatively related to responses within subgenual anterior and posterior cingulate cortex when processing high-intensity potential future positive and negative events. There was also a particularly marked negative relationship between CUD symptoms and blood oxygen level-dependent (BOLD) responses within visual and premotor cortices to high-intensity, negatively valenced potential future events. However, AUD symptom severity was not associated with dysfunction within these brain regions. These data indicate that relative risk/severity of CUD is associated with reduced responsiveness to future high-intensity events. This may impair decision-making where future significant consequences should guide response choice.

Dynamic functional connectivity between nucleus accumbens and the central executive network relates to chronic cannabis use.

The neural mechanisms of drug cue-reactivity regarding the temporal fluctuations of functional connectivity, namely the dynamic connectivity, are sparsely studied. Quantifying the task-modulated variability in dynamic functional connectivity at cue exposure can aid the understanding. We analyzed changes in dynamic connectivity in 54 adult cannabis users and 90 controls during a cannabis cue exposure task. The variability was measured as standard deviation in the (a) connectivity weights of the default mode, the central executive, and the salience networks and two reward loci (amygdalae and nuclei accumbens); and (b) topological indexes of the whole brain (global efficiency, modularity and network resilience). These were compared for the main effects of task conditions and the group (users vs. controls), and correlated with pre- and during-scan subjective craving. The variability of connectivity weights between the central executive network and nuclei accumbens was increased in users throughout the cue exposure task, and, was positively correlated with during-scan craving for cannabis. The variability of modularity was not different by groups, but positively correlated with prescan craving. The variability of dynamic connectivity during cannabis cue exposure task between the central executive network and the nuclei accumbens, and, the level of modularity, seem to relate to the neural underpinning of cannabis use and the subjective craving.

Interaction of Cannabis Use and Aging: From Molecule to Mind.

Given the aging Baby Boomer generation, changes in cannabis legislation, and the growing acknowledgment of cannabis for its therapeutic potential, it is predicted that cannabis use in the older population will escalate. It is, therefore, important to determine the interaction between the effects of cannabis and aging. The aim of this report is to describe the link between cannabis use and the aging brain. Our review of the literature found few and inconsistent empirical studies that directly address the impact of cannabis use on the aging brain. However, research focused on long-term cannabis use points toward cumulative effects on multimodal systems in the brain that are similarly affected during aging. Specifically, the effects of cannabis and aging converge on overlapping networks in the endocannabinoid, opioid, and dopamine systems that may affect functional decline particularly in the hippocampus and prefrontal cortex, which are critical areas for memory and executive functioning. To conclude, despite the limited current knowledge on the potential interactive effects between cannabis and aging, evidence from the literature suggests that cannabis and aging effects are concurrently present across several neurotransmitter systems. There is a great need for future research to directly test the interactions between cannabis and aging.

Testing the role of the posterior cingulate cortex in processing salient stimuli in cannabis users: an rTMS study.

The posterior cingulate cortex (PCC) and precuneus are hubs in the default mode network and play a role in processing external salient stimuli. Accordingly, activation in these regions has been associated with response to salient stimuli using drug cue-reactivity paradigms in substance using populations. These studies suggest that the PCC and precuneus may underlie deficits in processing salient stimuli that contribute toward the development of substance use disorders. The goal of this study was to directly test this hypothesis using repetitive transcranial magnetic stimulation (rTMS). Using a double-blind, placebo-controlled design, we used rTMS to target the PCC and precuneus with a double-cone coil at 10 Hz (high frequency) and 1 Hz (low frequency) in 10 adult cannabis users and 10 age- and sex-matched non-using controls. Electroencephalography data were collected before and after rTMS during a modified oddball paradigm with neutral, oddball, self-relevant, and cannabis-related stimuli. Cannabis users exhibited increased amplitude in P3 and faster latencies in the P3, N2, and P2 components in response to self-relevant stimuli compared to controls during baseline that normalized after rTMS. These results suggest that cannabis users exhibited heightened salience to external self-relevant stimuli that were modulated after rTMS. PCC dysfunction in cannabis users may be related to abnormalities in processing salient stimuli, such those during cue-reactivity, and provides a potential target for cannabis use disorder intervention.

Cannabis users exhibit increased cortical activation during resting state compared to non-users.

Studies have shown altered task-based brain functioning as a result of cannabis use. To date, however, whether similar alterations in baseline resting state and functional organization of neural activity are observable in cannabis users remains unknown. We characterized global resting state cortical activations and functional connectivity via electroencephalography (EEG) in cannabis users and related these activations to measures of cannabis use. Resting state EEG in the eyes closed condition was collected from age- and sex-matched cannabis users (N = 17; 6 females; mean age = 30.9 ±â€¯7.4 years) and non-using controls (N = 21; 9 females; mean age = 33.1 ±â€¯11.6 years). Power spectral density and spectral coherence were computed to determine differences in cortical activations and connectivity between the two groups in the delta (1-4Hz), theta (4-7 Hz), alpha (8-12 Hz), beta (13-30 Hz), and gamma (31-50 Hz) frequency bands. Cannabis users exhibited decreased delta and increased theta, beta, and gamma power compared to controls, suggesting increased cortical activation in resting state and a disinhibition of inhibitory functions that may interrupt cognitive processes. Cannabis users also exhibited increased interhemispheric and intrahemispheric coherence relative to controls, reduced mean network degree, and increased clustering coefficient in specific regions and frequencies. This increased cortical activity may indicate a loss of neural refinement and efficiency that may indicate a "noisy" brain. Lastly, measures related to cannabis use were correlated with spectral power and functional connectivity measures, indicating that specific electrophysiological signals are associated with cannabis use. These results suggest that there are differences in cortical activity and connectivity between cannabis users and non-using controls in the resting state that may be related to putative cognitive impairments and can inform effectiveness of intervention programs.

Brain intrinsic network connectivity in individuals with frequent tanning behavior.

BACKGROUND: Emergent studies suggest a bidirectional relationship between brain functioning and the skin. This neurocutaneous connection may be responsible for the reward response to tanning and, thus, may contribute to excessive tanning behavior. To date, however, this association has not yet been examined. OBJECTIVES: To explore whether intrinsic brain functional connectivity within the default mode network (DMN) is related to indoor tanning behavior. METHODS: Resting state functional connectivity (rsFC) was obtained in twenty adults (16 females) with a history of indoor tanning. Using a seed-based [(posterior cingulate cortex (PCC)] approach, the relationship between tanning severity and FC strength was assessed. Tanning severity was measured with symptom count from the Structured Clinical Interview for Tanning Abuse and Dependence (SITAD) and tanning intensity (lifetime indoor tanning episodes/years tanning). RESULTS: rsFC strength between the PCC and other DMN regions (left globus pallidus, left medial frontal gyrus, left superior frontal gyrus) is positively correlated with tanning symptom count. rsFC strength between the PCC and salience network regions (right anterior cingulate cortex, left inferior parietal lobe, left inferior temporal gyrus) is correlated with tanning intensity. CONCLUSION: Greater connectivity between tanning severity and DMN and salience network connectivity suggests that heightened self-awareness of salient stimuli may be a mechanism that underlies frequent tanning behavior. These findings add to the growing evidence of brain-skin connection and reflect dysregulation in the reward processing networks in those with frequent tanning.

Orbitofrontal cortex connectivity as a mechanism of adolescent behavior change.

An increasing number of studies have implicated the role of network functional connectivity in addiction. Yet, none have examined functional connectivity as a potential mechanism of adolescent behavior change. We examined the underlying neural mechanism of a promising treatment for adolescents, motivational interviewing (MI). We began by employing psychophysiological interaction (PPI) to evaluate network response in a sample of adolescent cannabis users (N=30). Next, we examined correlations between network connectivity and clinical metrics of treatment outcome. PPI analyses seeded on the orbitofrontal cortex (OFC) showed significant increases in functional connectivity across the inferior frontal gyrus (IFG), precentral gyrus, anterior and posterior cingulate gyrus, supplementary motor area (SMA), superior frontal gyrus, pallidus, caudate, and parahippocampal gyrus. Further, greater functional connectivity between the OFC and anterior cingulate/medial frontal gyrus was associated with less behavior change (e.g., greater post-treatment cannabis problems). These data support the role of the OFC network as a mechanism of adolescent treatment response.

Long-term effects of marijuana use on the brain.

Questions surrounding the effects of chronic marijuana use on brain structure continue to increase. To date, however, findings remain inconclusive. In this comprehensive study that aimed to characterize brain alterations associated with chronic marijuana use, we measured gray matter (GM) volume via structural MRI across the whole brain by using voxel-based morphology, synchrony among abnormal GM regions during resting state via functional connectivity MRI, and white matter integrity (i.e., structural connectivity) between the abnormal GM regions via diffusion tensor imaging in 48 marijuana users and 62 age- and sex-matched nonusing controls. The results showed that compared with controls, marijuana users had significantly less bilateral orbitofrontal gyri volume, higher functional connectivity in the orbitofrontal cortex (OFC) network, and higher structural connectivity in tracts that innervate the OFC (forceps minor) as measured by fractional anisotropy (FA). Increased OFC functional connectivity in marijuana users was associated with earlier age of onset. Lastly, a quadratic trend was observed suggesting that the FA of the forceps minor tract initially increased following regular marijuana use but decreased with protracted regular use. This pattern may indicate differential effects of initial and chronic marijuana use that may reflect complex neuroadaptive processes in response to marijuana use. Despite the observed age of onset effects, longitudinal studies are needed to determine causality of these effects.

fMRI study of neural sensitization to hedonic stimuli in long-term, daily cannabis users.

Although there is emergent evidence illustrating neural sensitivity to cannabis cues in cannabis users, the specificity of this effect to cannabis cues as opposed to a generalized hyper-sensitivity to hedonic stimuli has not yet been directly tested. Using fMRI, we presented 53 daily, long-term cannabis users and 68 non-using controls visual and tactile cues for cannabis, a natural reward, and, a sensory-perceptual control object to evaluate brain response to hedonic stimuli in cannabis users. The results showed an interaction between group and reward type such that the users had greater response during cannabis cues relative to natural reward cues (i.e., fruit) in the orbitofrontal cortex, striatum, anterior cingulate gyrus, and ventral tegmental area compared to non-users (cluster-threshold z = 2.3, P < 0.05). In the users, there were positive brain-behavior correlations between neural response to cannabis cues in fronto-striatal-temporal regions and subjective craving, marijuana-related problems, withdrawal symptoms, and levels of THC metabolites (cluster-threshold z = 2.3, P < 0.05). These findings demonstrate hyper-responsivity, and, specificity of brain response to cannabis cues in long-term cannabis users that are above that of response to natural reward cues. These observations are concordant with incentive sensitization models suggesting sensitization of mesocorticolimbic regions and disruption of natural reward processes following drug use. Although the cross-sectional nature of this study does not provide information on causality, the positive correlations between neural response and indicators of cannabis use (i.e., THC levels) suggest that alterations in the reward system are, in part, related to cannabis use. Hum Brain Mapp 37:3431-3443, 2016. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

The hyper-sentient addict: an exteroception model of addiction.

BACKGROUND: Exteroception involves processes related to the perception of environmental stimuli important for an organism's ability to adapt to its environment. As such, exteroception plays a critical role in conditioned response. In addiction, behavioral and neuroimaging studies show that the conditioned response to drug-related cues is often associated with alterations in brain regions including the precuneus/posterior cingulate cortex, an important node within the default mode network dedicated to processes such as self-monitoring. OBJECTIVE: This review aimed to summarize the growing, but largely fragmented, literature that supports a central role of exteroceptive processes in addiction. METHODS: We performed a systematic review of empirical research via PubMed and Google Scholar with keywords including 'addiction', 'exteroception', 'precuneus', and 'self-awareness', to identify human behavioral and neuroimaging studies that report mechanisms of self-awareness in healthy populations, and altered self-awareness processes, specifically exteroception, in addicted populations. RESULTS: Results demonstrate that exteroceptive processes play a critical role in conditioned cue response in addiction and serve as targets for interventions such as mindfulness training. Further, a hub of the default mode network, namely, the precuneus, is (i) consistently implicated in exteroceptive processes, and (ii) widely demonstrated to have increased activation and connectivity in addicted populations. CONCLUSION: Heightened exteroceptive processes may underlie cue-elicited craving, which in turn may lead to the maintenance and worsening of substance use disorders. An exteroception model of addiction provides a testable framework from which novel targets for interventions can be identified.

Age-related increase of resting metabolic rate in the human brain.

With age, many aspects of the brain structure undergo a pronounced decline, yet individuals generally function well until advanced old age. There appear to be several compensatory mechanisms in brain aging, but their precise nature is not well characterized. Here we provide evidence that the brain of older adults expends more energy when compared to younger adults, as manifested by an age-related increase (P=0.03) in cerebral metabolic rate of oxygen (CMRO2) (N=118, men=56, ages 18 to 74). We further showed that, before the mean menopausal age of 51years old, female and male groups have similar rates of CMRO2 increase (P=0.015) and there was no interaction between age and sex effects (P=0.85). However, when using data from the entire age range, women have a slower rate of CMRO2 change when compared to men (P<0.001 for age×sex interaction term). Thus, menopause and estrogen level may have played a role in this sex difference. Our data also revealed a possible circadian rhythm of CMRO2 in that brain metabolic rate is greater at noon than in the morning (P=0.02). This study reveals a potential neurobiological mechanism for age-related compensation in brain function and also suggests a sex-difference in its temporal pattern.

MRI assessment of cerebral oxygen metabolism in cocaine-addicted individuals: hypoactivity and dose dependence.

Long-term cocaine use is known to negatively impact neural and cerebrovascular systems. However, the use of imaging markers to separately assess these parameters remains challenging. The primary reason is that most functional imaging markers, such as cerebral blood flow, functional connectivity, and task-evoked functional MRI, are known to reflect a complex interplay between neural and vascular components, thus the interpretation of the results is not straightforward. The goal of the present study is to examine neural-activity-specific changes in cocaine addiction, using cerebral metabolic rate of oxygen (CMRO2) as a surrogate marker of aggregated neural activity. We applied a recently developed CMRO2 technique in 13 cocaine-addicted subjects and 13 age- and gender-matched control subjects, and examined the impact of long-term cocaine use on CMRO2. Our results showed that CMRO2 in cocaine-addicted subjects (152 ± 16 µmol/100 g/min) is significantly lower (p = 0.031) than that in controls (169 ± 20 µmol/100 g/min). Furthermore, the severity of this decreased metabolism is associated with lifetime cocaine use (p = 0.05). Additionally, the CMRO2 reduction was accompanied by a trend of decrease in cerebral blood flow (p = 0.058), but venous oxygenation was unaffected (p = 0.96), which suggested that the CMRO2 change may be attributed to a vascular deficiency in chronic cocaine users. To our knowledge, this is the first study to measure CMRO2 in cocaine-addicted individuals. Our findings suggest that CMRO2 may be a promising approach for assessing the long-term effects of cocaine use on the brain.

Unique aspects of impulsive traits in substance use and overeating: specific contributions of common assessments of impulsivity.

UNLABELLED: Abstract Background: Impulsivity is a complex trait often studied in substance abuse and overeating disorders, but the exact nature of impulsivity traits and their contribution to these disorders are still debated. Thus, understanding how to measure impulsivity is essential for comprehending addictive behaviors. OBJECTIVES: Identify unique impulsivity traits specific to substance use and overeating. METHODS: Impulsive Sensation Seeking (ImpSS) and Barratt's Impulsivity scales (BIS) Scales were analyzed with a non-parametric factor analytic technique (discriminant correspondence analysis) to identify group-specific traits on 297 individuals from five groups: Marijuana (n = 88), Nicotine (n = 82), Overeaters (n = 27), Marijuauna + Nicotine (n = 63), and CONTROLs (n = 37). RESULTS: A significant overall factor structure revealed three components of impulsivity that explained respectively 50.19% (pperm < 0.0005), 24.18% (pperm < 0.0005), and 15.98% (pperm < 0.0005) of the variance. All groups were significantly different from one another. When analyzed together, the BIS and ImpSS produce a multi-factorial structure that identified the impulsivity traits specific to these groups. The group specific traits are (1) CONTROL: low impulse, avoids thrill-seeking behaviors; (2) Marijuana: seeks mild sensation, is focused and attentive; (3) Marijuana + Nicotine: pursues thrill-seeking, lacks focus and attention; (4) Nicotine: lacks focus and planning; (5) Overeating: lacks focus, but plans (short and long term). CONCLUSIONS: Our results reveal impulsivity traits specific to each group. This may provide better criteria to define spectrums and trajectories - instead of categories - of symptoms for substance use and eating disorders. Defining symptomatic spectrums could be an important step forward in diagnostic strategies.

Unlocking the age-old secrets of reward and substance use.

Although substance use is widespread across the lifespan from early adolescence to older adulthood, the prevalence of substance use disorder (SUD) differs between age groups. These age differences in SUD rates necessitate an investigation into how age moderates reward sensitivity, and consequently influences the risks and consequences related to substance use. This theoretical review integrates evidence from the literature to address the dynamic interplay between age and reward in the context of substance use. Overall, increasing evidence demonstrates that age moderates reward sensitivity and underlying reward system neurobiology. Reward sensitivity undergoes a non-linear trajectory across the lifespan. Low levels of reward sensitivity are associated with childhood and late adulthood. In contrast, high levels are associated with early to late adolescence, followed by a decline in the twenties. These fluctuations in reward sensitivity across the lifespan contribute to complex associations with substance use. This lends support to adolescence and young adulthood as vulnerable periods for the risk of subsequent SUD. More empirical research is needed to investigate reward sensitivity during SUD maintenance and recovery. Future research should also involve larger sample sizes and encompass a broader range of age groups, including older adults.

Residual and enduring effects of cannabis use on cognitive and psychomotor function: A study of adults during unrestricted cannabis use, short-term abstinence, and protracted abstinence.

The impact of cannabis on cognitive and psychomotor function is important to understand, given the role of the endocannabinoid system in these critical processes. The literature has shown robust acute negative effects of cannabis on cognition and psychomotor skills during intoxication, and to a lesser degree, persisting effects following short-term abstinence up to 4 weeks. However, whether these decrements resolve after long-term cessation of use remains unclear. We evaluated cognitive and psychomotor function in 31 adults with current cannabis use during unrestricted use (UNR) and after a 3-day abstinence (RES), 23 adults with former cannabis use (> 90 days abstinent; FU), and 58 nonusing controls (CON) using the cognition and motor batteries of the National Institutes of Health Toolbox. Linear mixed models showed no significant differences in cognitive and motor performance between UNR, RES, and FU groups. Group effects emerged such that CON outperformed UNR on the Oral Reading Recognition Test, and CON outperformed both UNR and RES on the Picture Vocabulary Test. In terms of psychomotor function, FU, RES, and UNR performed better than CON on the Grip Strength Test. In this comprehensive examination of cognitive and psychomotor performance in adults with cannabis use with 3 days to > 90 days of abstinence, our results indicated that the cognitive impacts of chronic, heavy cannabis use are observable during short-term abstinence but remit after > 90 days of abstinence. This highlights widespread impacts of cannabis use abstinence across cognitive and psychomotor domains. Future studies are needed to evaluate whether these effects are also observable with use reduction, as opposed to abstinence. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Parameter Space and Potential for Biomarker Development in 25 Years of fMRI Drug Cue Reactivity: A Systematic Review.

Importance: In the last 25 years, functional magnetic resonance imaging drug cue reactivity (FDCR) studies have characterized some core aspects in the neurobiology of drug addiction. However, no FDCR-derived biomarkers have been approved for treatment development or clinical adoption. Traversing this translational gap requires a systematic assessment of the FDCR literature evidence, its heterogeneity, and an evaluation of possible clinical uses of FDCR-derived biomarkers. Objective: To summarize the state of the field of FDCR, assess their potential for biomarker development, and outline a clear process for biomarker qualification to guide future research and validation efforts. Evidence Review: The PubMed and Medline databases were searched for every original FDCR investigation published from database inception until December 2022. Collected data covered study design, participant characteristics, FDCR task design, and whether each study provided evidence that might potentially help develop susceptibility, diagnostic, response, prognostic, predictive, or severity biomarkers for 1 or more addictive disorders. Findings: There were 415 FDCR studies published between 1998 and 2022. Most focused on nicotine (122 [29.6%]), alcohol (120 [29.2%]), or cocaine (46 [11.1%]), and most used visual cues (354 [85.3%]). Together, these studies recruited 19 311 participants, including 13 812 individuals with past or current substance use disorders. Most studies could potentially support biomarker development, including diagnostic (143 [32.7%]), treatment response (141 [32.3%]), severity (84 [19.2%]), prognostic (30 [6.9%]), predictive (25 [5.7%]), monitoring (12 [2.7%]), and susceptibility (2 [0.5%]) biomarkers. A total of 155 interventional studies used FDCR, mostly to investigate pharmacological (67 [43.2%]) or cognitive/behavioral (51 [32.9%]) interventions; 141 studies used FDCR as a response measure, of which 125 (88.7%) reported significant interventional FDCR alterations; and 25 studies used FDCR as an intervention outcome predictor, with 24 (96%) finding significant associations between FDCR markers and treatment outcomes. Conclusions and Relevance: Based on this systematic review and the proposed biomarker development framework, there is a pathway for the development and regulatory qualification of FDCR-based biomarkers of addiction and recovery. Further validation could support the use of FDCR-derived measures, potentially accelerating treatment development and improving diagnostic, prognostic, and predictive clinical judgments.